In cancer chemotherapy today, a variety of anticancer drugs such as alkylating agents, topoisomerase inhibitors, antimetabolites, cytoskeletal system inhibitors, enzymes, hormones, antihormones, antibiotics, and plant products are being employed.
Referring to anticancer hormones, particularly stilbenes having a nuclear skeletal structure resembling that of the compound of the present invention, stilbestrol phosphate and tamoxifen and so on have been used in the treatment of cancer of the prostate, breast and other tissues but they are not fully satisfactory from the standpoint of efficacy and in view of the adverse effects associated with their hormonal activity.
Antimicrotubule agents or tubulin agonists have potent anticancer activity with a broad anticancer spectrum and constitute a clinically important class of drugs.
The inhibition of tubulin polymerization is attracting attention of late as a mechanism of action of anticancer agents. The microtubule is an ubiquitous intracellular structure and, as a major component of the mitotic spindle, plays an important role in cell division. An antimicrotubule agent binds to the tublin protein of the microtubule and disrupts the dynamics of the microtubule by orienting it either in the direction of assembly or in that of disassembly, thus manifesting its anticancer activity. Vinca alkaloids, which are of plant origin, are known as representative tubulin polymerization-inhibitory anticancer agents and recently taxols are gathering attention because of their potent anticancer efficacy associated with promotion of tubulin polymerization. Being derived from plants, these compounds have availability problems. Such anticancer drugs acting on microtubules are available as injections which cannot be conveniently used and, because of their side effects, are not being used in multiple-dose regimens. Quite recently, the low molecular weight substance E7010 (Cancer and Chemotherapy, 1993 20: 34-41, JP Kokai H5-39256) has been discovered and clinical trials with the compound are now being watched by many with much interest.
It is reported that stilbene derivatives represented by (Z)-3,4,5-trimethoxy-4'-methoxystilbene as well as dihydrostilbene derivatives, which have a stilbene nucleus similar to that of the compound of the present invention, have tubulin polymerization-inhibitory activity (J. Med. Chem. 1991, 34, 2579).
Meanwhile, it is reported that hydroxamic acid derivatives substituted by a phenylethenyl-heterocyclic group show antiallergic activity (Eur. J. Med. Chem. 1985, 20, 487-491). There also is a report on the interaction between tetrahydrostilbazole and monoamine oxidase (J. Med. Chem. 1994, 37, 151-157).